Muscle-invasive and Metastatic Bladder Cancer

1 Witjes (Chair), Bruins, A. Carri n, R. Cathomas, Comp rat, Efstathiou, R. Fietkau, G. Gakis, van der Heijden, A. Lorch, Meijer, Milowsky, V. Panebianco, M. Rink, Thalmann, E. Veskim ePatient Advocates: J. Redlef, S. S bj rnsenGuidelines Associates: E. Linares Espin s, Mertens, M. Rouanne, Y. Neuzillet European Association of Urology 2022 Muscle-invasive and Metastatic Bladder CancerEAU Guidelines onMUSCLE-INVASIVE AND Metastatic Bladder Cancer - LIMITED UPDATE MARCH 20222 TABLE OF CONTENTS PAGE1.

2 INTRODUCTION 6 Aims and scope 6 Panel composition 6 Available publications 6 Publication history and summary of changes 6 Publication history 6 Summary of changes 62. METHODS 9 Data identification 9 Peer-review 9 Lay review 9 Future goals 103. EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY 10 Epidemiology 10 Aetiology 10 Tobacco smoking 10 Occupational exposure to chemicals 11 Radiotherapy 11 Dietary factors 11 Metabolic disorders 11 Bladder schistosomiasis and chronic urinary tract infection 11 Gender 12 Genetic factors 12 Summary of evidence and guidelines for epidemiology and risk

3 Factors 12 Pathology 13 Handling of transurethral resection and cystectomy specimens 13 Pathology of Muscle-invasive Bladder Cancer 13 Guidelines for the assessment of tumour specimens 14 EAU-ESMO consensus statements on the management of advanced- and variant Bladder Cancer 144. STAGING AND CLASSIFICATION SYSTEMS 14 Pathological staging 14 Tumour, node, metastasis classification 145. DIAGNOSTIC EVALUATION 15 Primary diagnosis 15 Symptoms 15 Physical examination 15 Bladder imaging 15 urinary cytology 16 Cystoscopy 16 Transurethral resection of invasive Bladder tumours 16 Summary of evidence and guidelines for the primary assessment of presumably invasive Bladder tumours 17 EAU-ESMO consensus statements on the management of advanced- and variant Bladder Cancer 17 Imaging for

4 Staging of MIBC 17 Local staging of MIBC 18 Magnetic resonance imaging for local staging of MIBC 18 CT imaging for local staging of MIBC 18 Imaging of lymph nodes in MIBC 18 Upper urinary tract urothelial carcinoma 18 Computed tomography urography 18 Magnetic resonance urography 19 Distant metastases at sites other than lymph nodes 193 Muscle-invasive AND Metastatic Bladder Cancer - LIMITED UPDATE MARCH 2022 Future developments 19 Summary of evidence and guidelines for staging in Muscle-invasive Bladder Cancer 19 MIBC and health status 19 Evaluation of comorbidity, frailty and cognition 20 Comorbidity scales, anaesthetic risk classification and geriatric assessment 21 Summary of evidence and guidelines for comorbidity scales 226.

5 MARKERS 23 Introduction 23 Prognostic markers 23 Histopathological and clinical markers 23 Molecular markers 23 Molecular subtypes based on the Cancer Genome Atlas cohort 23 Predictive markers 24 Clinical and histopathological markers 24 Molecular markers 24 Conclusion 25 Summary of evidence for urothelial markers 257. DISEASE MANAGEMENT 25 Neoadjuvant therapy 25 Introduction 25 Role of cisplatin-based chemotherapy 25 Summary of available data 26 The role of imaging and predictive biomarkers 27 Role of neoadjuvant immunotherapy 27 Summary of evidence and guidelines for neoadjuvant therapy 27 Pre- and post-operative radiotherapy in Muscle-invasive Bladder Cancer 28 Post-operative radiotherapy 28 Pre-operative radiotherapy 28 Summary of evidence and

6 Guidelines for pre- and post-operative radiotherapy 28 radical surgery and urinary diversion 29 Removal of the tumour-bearing Bladder 29 Introduction 29 radical cystectomy : timing 29 radical cystectomy : indications 29 radical cystectomy : technique and extent 29 radical cystectomy in men 29 Concomitant prostate Cancer 29 Sexual-preserving techniques 29 Summary of evidence and recommendations for sexual-preserving techniques in men 30 radical cystectomy in women 30 Summary of evidence and recommendations for sexual-preserving techniques in women 31 Lymphadenectomy.

7 Role and extent 31 Laparoscopic/robotic-assisted laparoscopic cystectomy 32 Laparoscopic radical cystectomy versus robot-assisted radical cystectomy 33 Summary of evidence and guidelines for laparoscopic/robotic- assisted laparoscopic cystectomy 33 urinary diversion after radical cystectomy 34 Patient selection and preparations for surgery 34 Different types of urinary diversion 35 Uretero-cutaneostomy 35 Ileal conduit 35 Orthotopic neobladder 36 Morbidity and mortality 36 Survival 38 Muscle-invasive AND Metastatic Bladder Cancer - LIMITED UPDATE MARCH 20224 Impact of hospital and surgeon volume on treatment outcomes 38 Summary of evidence and guidelines for radical cystectomy and urinary diversion 39 Unresectable tumours 40 Palliative cystectomy 40 Guidelines for unresectable tumours 40 EAU-ESMO consensus statements on the management of

8 Advanced- and variant Bladder Cancer 41 Supportive care 41 Obstruction of the upper urinary tract 41 Bleeding and pain 41 Bladder -sparing treatments for localised disease 41 Transurethral resection of Bladder tumour 41 Guideline for transurethral resection of Bladder tumour 41 External beam radiotherapy 41 Summary of evidence and guideline for external beam radiotherapy 42 EAU-ESMO consensus statements on the management of advanced- and variant Bladder Cancer 42 Chemotherapy 42 Summary of evidence and guideline for chemotherapy 43 Trimodality Bladder -preserving treatment 43 Summary of evidence and guidelines for trimodality Bladder - preserving treatment 45 EAU-ESMO consensus statements on the management of advanced- and variant Bladder Cancer 45 Adjuvant therapy 46 Role of adjuvant platinum-based chemotherapy 46 Role of adjuvant immunotherapy 46 Summary of evidence and guidelines for adjuvant therapy 47

9 Metastatic disease 47 Introduction 47 First-line systemic therapy for Metastatic disease 47 First-line chemotherapy in patients fit for cisplatin 48 First-line chemotherapy in patients fit for carboplatin (but unfit for cisplatin) 48 Integration of immunotherapy in the first-line chemotherapy treatment of patients fit for platinum (cisplatin or carboplatin) 49 Immunotherapy combination approaches 49 Use of first-line single-agent immunotherapy in patients unfit for cisplatinum-based chemotherapy 49 Switch maintenance with immunotherapy after platinum-based chemotherapy 49 Treatment of patients unfit for any platinum-based chemotherapy 50 S